Ornithine transcarbamylase deficiency

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Ornithine transcarbamylase deficiency
Other namesOTC deficiency, Ornithine Carbamoyltransferase Deficiency Disease.
L-Ornithine structure.svg
Structure of L-Ornithine
Specialty Medical genetics, metabolic syndrome, pediatrics   OOjs UI icon edit-ltr-progressive.svg
Symptoms Tachypnea, vomiting, lethargy, loss of appetite, early morning headaches, and confusion. [1]
Complications Liver failure, severe hyperammonemic encephalopathy, coma, death, intellectual, and physical disabilities. [1]
Causes Genetic mutation. [1]
Diagnostic method Liver function tests, genetic testing, and a liver biopsy. [1]
Differential diagnosis urea cycle disorders, fulminant hepatitis, Citrin deficiency, and hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. [2]
TreatmentHydration, arginine, and hemodialysis. [1]
Prognosis 50% of infants with OTC deficiency die. [1]
Frequency1 in 14,000 to 1 in 77,000 people. [3]

Ornithine transcarbamylase deficiency also known as OTC deficiency is the most common urea cycle disorder in humans. Ornithine transcarbamylase, the defective enzyme in this disorder, is the final enzyme in the proximal portion of the urea cycle, responsible for converting carbamoyl phosphate and ornithine into citrulline. OTC deficiency is inherited in an X-linked recessive manner, meaning males are more commonly affected than females.

Contents

In severely affected individuals, ammonia concentrations increase rapidly causing ataxia, lethargy and death without rapid intervention. OTC deficiency is diagnosed using a combination of clinical findings and biochemical testing, while confirmation is often done using molecular genetics techniques.

Once an individual has been diagnosed, the treatment goal is to avoid precipitating episodes that can cause an increased ammonia concentration. The most common treatment combines a low protein diet with nitrogen scavenging agents. Liver transplant is considered curative for this disease. Experimental trials of gene therapy using adenoviral vectors resulted in the death of one participant, Jesse Gelsinger, and have been discontinued.

Signs and symptoms

As with several other metabolic conditions, OTC deficiency can have variable presentations, regarding age of onset and the severity of symptoms. This compounded when considering heterozygous females and the possibility of non-random X-inactivation. In the classic and most well-known presentation, a male infant appears well initially, but by the second day of life they are irritable, lethargic and stop feeding. A metabolic encephalopathy develops, and this can progress to coma and death without treatment. [4] Ammonia is only toxic to the brain, other tissues can handle elevated ammonia concentrations without problems. [5]

Later onset forms of OTC deficiency can have variable presentations. Although late onset forms of the disease are often considered milder than the classic infantile presentation, any affected individual is at risk for an episode of hyperammonemia that could still be life-threatening, if presented with the appropriate stressors. [6] These patients will often present with headaches, nausea, vomiting, delayed growth and a variety of psychiatric symptoms (confusion, delirium, aggression, or self-injury). [5] A detailed dietary history of an affected individual with undiagnosed OTC deficiency will often reveal a history of protein avoidance. [6]

The prognosis of a patient with severe OTC deficiency is well correlated with the length of the hyperammonemic period rather than the degree of hyperammonemia or the presence of other symptoms, such as seizures. [6] Even for patients with late onset forms of the disease, their overall clinical picture is dependent on the extent of hyperammonemia they have experienced, even if it has remained unrecognized. [5]

Genetics

OTC deficiency is caused by mutations in the OTC gene, which is located on the X chromosome. [7] OTC codes for the mitochondrial enzyme ornithine transcarbamylase, which is expressed only in liver. The functional enzyme consists of three identical subunits. [8] OTC is the last enzyme in the proximal portion of the urea cycle, which consists of the reactions that take place in the mitochondria. The substrates of the reaction catalyzed by ornithine transcarbamylase are ornithine and carbamyl phosphate, while the product is citrulline. [5]

There are no common mutations that cause disease, however 10 - 15% of disease causing mutations are deletions. [7] It is inherited in an X-linked recessive manner, meaning males are more commonly affected than females. Females who carry a defective copy of the gene can be severely affected or asymptomatic, largely depending on the random nature of X-inactivation. [7] There is some degree of genotype — phenotype correlation with OTC deficiency, but this depends on a number of situations. Individuals with milder mutations, often associated with late onset disease can still present with severe illness when exposed to sufficient metabolic stress. Correlations are more difficult to ascertain in females, since the residual activity of OTC in the liver is impacted not only by the nature of the mutation, but also by the random pattern of X-inactivation. [6] OTC deficiency is estimated to be the most common urea cycle disorder. [6] An exact incidence is difficult to calculate, due to the varying clinical presentations of later onset forms of the disease. Early estimates of the incidence were as high as 1:14,000 live births, however later studies have decreased these estimates to approximately 1:60,000 - 1:72,000. [6]

Diagnosis

In individuals with marked hyperammonemia, a urea cycle disorder is usually high on the list of possible causes. While the immediate focus is lowering the patient's ammonia concentrations, identifying the specific cause of increased ammonia levels is key as well.[ citation needed ]

Diagnostic testing for OTC deficiency, or any individual with hyperammonemia involves plasma and urine amino acid analysis, urine organic acid analysis (to identify the presence or absence of orotic acid, as well as rule out an organic acidemia) and plasma acylcarnitines (will be normal in OTC deficiency, but can identify some other causes of hyperammonemia). An individual with untreated OTC deficiency will show decreased citrulline and arginine concentrations (because the enzyme block is proximal to these intermediates) and increased orotic acid. [4] The increased orotic acid concentrations result from the buildup of carbamoyl phosphate. This biochemical phenotype (increased ammonia, low citrulline and increased orotic acid) is classic for OTC deficiency, but can also be seen in neonatal presentations of ornithine aminotransferase deficiency. [4] Only severely affected males consistently demonstrate this classic biochemical phenotype.[ citation needed ]

Heterozygous females can be difficult to diagnose. With the rise of sequencing techniques, molecular testing has become preferred, particularly when the disease causing mutations in the family are known. [7] Historically, heterozygous females were often diagnosed using an allopurinol challenge. In a female with reduced enzyme activity, an oral dose of allopurinol would be metabolized to oxypurinol ribonucleotide, which blocks the pyrimidine biosynthetic pathway. When this induced enzymatic block is combined with reduced physiologic enzyme activity as seen in heterozygotes, the elevation of orotic acid could be used to differentiate heterozygotes from unaffected individuals. This test was not universally effective, as it had both false negative and false positive results. [5]

Ornithine transcarbamylase is only expressed in the liver, thus performing an enzyme assay to confirm the diagnosis requires a liver biopsy. Before molecular genetic testing was commonly available, this was one of the only methods for confirmation of a suspected diagnosis. In cases where prenatal diagnosis was requested, a fetal liver biopsy used to be required to confirm if a fetus was affected. [4] Modern molecular techniques have eliminated this need, and gene sequencing is now the preferred method of diagnosis in asymptomatic family members after the diagnosis has been confirmed in a proband. [6] [7]

Treatment

The treatment goal for individuals affected with OTC deficiency is the avoidance of hyperammonemia. This can be accomplished through a strictly controlled low-protein diet, as well as preventative treatment with nitrogen scavenging agents such as sodium benzoate. The goal is to minimize the nitrogen intake while allowing waste nitrogen to be excreted by alternate pathways. [7] Arginine is typically supplemented as well, in an effort to improve the overall function of the urea cycle. [7] If a hyperammonemic episode occurs, the aim of treatment is to reduce the individual's ammonia levels as soon as possible. In extreme cases, this can involve hemodialysis. [4]

Gene therapy had been considered a possibility for curative treatment for OTC deficiency, and clinical trials were taking place at the University of Pennsylvania in the late 1990s. These were halted after the death of Jesse Gelsinger, a young man taking part in a phase I trial using an adenovirus vector. [9] Currently, the only option for curing OTC deficiency is a liver transplant, which restores normal enzyme activity. [10] A 2005 review of 51 patients with OTC deficiency who underwent liver transplant estimated 5-year survival rates of greater than 90%. [10] Severe cases of OTC deficiency are typically evaluated for liver transplant by 6 months of age. [6]

Prognosis

A 1999 retrospective study of 74 cases of neonatal onset found that 32 (43%) patients died during their first hyperammonemic episode. Of those who survived, less than 20% survived to age 14. Few of these patients received liver transplants. [11]

Society and culture

Ornithine transcarbamylase deficiency was the final diagnosis of a patient treated in the 15th episode of 1st season of House, M. D. It was also the final diagnosis of a patient that died in the 3rd episode of 3rd season of Chicago Med.[ citation needed ]

Related Research Articles

The urea cycle (also known as the ornithine cycle) is a cycle of biochemical reactions that produces urea (NH2)2CO from ammonia (NH3). Animals that use this cycle, mainly amphibians and mammals, are called ureotelic.

<span class="mw-page-title-main">Ornithine</span> Chemical compound

Ornithine is a non-proteinogenic α-amino acid that plays a role in the urea cycle. Ornithine is abnormally accumulated in the body in ornithine transcarbamylase deficiency. The radical is ornithyl.

<span class="mw-page-title-main">Ornithine transcarbamylase</span> Mammalian protein found in Homo sapiens

Ornithine transcarbamylase (OTC) is an enzyme that catalyzes the reaction between carbamoyl phosphate (CP) and ornithine (Orn) to form citrulline (Cit) and phosphate (Pi). There are two classes of OTC: anabolic and catabolic. This article focuses on anabolic OTC. Anabolic OTC facilitates the sixth step in the biosynthesis of the amino acid arginine in prokaryotes. In contrast, mammalian OTC plays an essential role in the urea cycle, the purpose of which is to capture toxic ammonia and transform it into urea, a less toxic nitrogen source, for excretion.

<span class="mw-page-title-main">Carbamoyl phosphate</span> Chemical compound

Carbamoyl phosphate is an anion of biochemical significance. In land-dwelling animals, it is an intermediary metabolite in nitrogen disposal through the urea cycle and the synthesis of pyrimidines. Its enzymatic counterpart, carbamoyl phosphate synthetase I, interacts with a class of molecules called sirtuins, NAD dependent protein deacetylases, and ATP to form carbamoyl phosphate. CP then enters the urea cycle in which it reacts with ornithine to form citrulline.

<span class="mw-page-title-main">Hyperammonemia</span> Medical condition

Hyperammonemia, or high ammonia levels, is a metabolic disturbance characterised by an excess of ammonia in the blood. It is a dangerous condition that may lead to brain injury and death. It may be primary or secondary.

<span class="mw-page-title-main">Orotic acid</span> Chemical compound synthesized in the body via a mitochondrial enzyme

Orotic acid is a pyrimidinedione and a carboxylic acid. Historically, it was believed to be part of the vitamin B complex and was called vitamin B13, but it is now known that it is not a vitamin.

<span class="mw-page-title-main">Citrullinemia</span> Medical condition

Citrullinemia is an autosomal recessive urea cycle disorder that causes ammonia and other toxic substances to accumulate in the blood.

<span class="mw-page-title-main">Lysinuric protein intolerance</span> Medical condition

Lysinuric protein intolerance (LPI) is an autosomal recessive metabolic disorder affecting amino acid transport. It is characterised by the body's inability to properly digest and use certain proteins. This condition leads to various metabolic complications and is typically diagnosed in infancy or early childhood.

<span class="mw-page-title-main">Argininosuccinic aciduria</span> Medical condition

Argininosuccinic aciduria is an inherited disorder that causes the accumulation of argininosuccinic acid in the blood and urine. Some patients may also have an elevation of ammonia, a toxic chemical, which can affect the nervous system. Argininosuccinic aciduria may become evident in the first few days of life because of high blood ammonia, or later in life presenting with "sparse" or "brittle" hair, developmental delay, and tremors.

<span class="mw-page-title-main">Argininosuccinate lyase</span> Mammalian protein found in Homo sapiens

The enzyme argininosuccinate lyase (EC 4.3.2.1, ASL, argininosuccinase; systematic name 2-(N ω-L-arginino)succinate arginine-lyase (fumarate-forming)) catalyzes the reversible breakdown of argininosuccinate:

<span class="mw-page-title-main">Methylmalonyl-CoA mutase deficiency</span> Medical condition

Methylmalonyl-CoA mutase is a mitochondrial homodimer apoenzyme that focuses on the catalysis of methylmalonyl CoA to succinyl CoA. The enzyme is bound to adenosylcobalamin, a hormonal derivative of vitamin B12 in order to function. Methylmalonyl-CoA mutase deficiency is caused by genetic defect in the MUT gene responsible for encoding the enzyme. Deficiency in this enzyme accounts for 60% of the cases of methylmalonic acidemia.

<span class="mw-page-title-main">N-Acetylglutamate synthase deficiency</span> Medical condition

N-Acetylglutamate synthase deficiency is an autosomal recessive urea cycle disorder.

Carbamoyl phosphate synthetase I deficiency is an autosomal recessive metabolic disorder that causes ammonia to accumulate in the blood due to a lack of the enzyme carbamoyl phosphate synthetase I. Ammonia, which is formed when proteins are broken down in the body, is toxic if the levels become too high. The nervous system is especially sensitive to the effects of excess ammonia.

<span class="mw-page-title-main">Ornithine translocase deficiency</span> Medical condition

Ornithine translocase deficiency, also called hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, is a rare autosomal recessive urea cycle disorder affecting the enzyme ornithine translocase, which causes ammonia to accumulate in the blood, a condition called hyperammonemia.

<span class="mw-page-title-main">Orotic aciduria</span> Medical condition

Orotic aciduria is a disease caused by an enzyme deficiency, resulting in a decreased ability to synthesize pyrimidines. It was the first described enzyme deficiency of the de novo pyrimidine synthesis pathway.

<span class="mw-page-title-main">Argininemia</span> Medical condition

Argininemia is an autosomal recessive urea cycle disorder where a deficiency of the enzyme arginase causes a buildup of arginine and ammonia in the blood. Ammonia, which is formed when proteins are broken down in the body, is toxic if levels become too high; the nervous system is especially sensitive to the effects of excess ammonia.

Transient hyperammonemia of the newborn (THAN) is an idiopathic disorder occasionally present in preterm newborns but not always symptomatic. Continuous dialysis or hemofiltration have proven to be the most effective treatment. Nutritional support and sodium benzoate have also been used to treat THAN.

<span class="mw-page-title-main">Ornithine aminotransferase deficiency</span> Medical condition

Ornithine aminotransferase deficiency is an inborn error of ornithine metabolism, caused by decreased activity of the enzyme ornithine aminotransferase. Biochemically, it can be detected by elevated levels of ornithine in the blood. Clinically, it presents initially with poor night vision, which slowly progresses to total blindness. It is believed to be inherited in an autosomal recessive manner. Approximately 200 known cases have been reported in the literature. The incidence is highest in Finland, estimated at 1:50,000.

<span class="mw-page-title-main">Homocitrulline</span> Chemical compound

L-Homocitrulline is an amino acid and can be detected in larger amounts in the urine of individuals with urea cycle disorders. At present, it is thought that the depletion of the ornithine supply causes the accumulation of carbamyl-phosphate in the urea cycle which may be responsible for the enhanced synthesis of homocitrulline and homoarginine. Both amino acids can be detected in urine. Amino acid analysis allows for the quantitative analysis of these amino acid metabolites in biological fluids such as urine or blood.

<span class="mw-page-title-main">Citrullinemia type I</span> Medical condition

Citrullinemia type I (CTLN1), also known as arginosuccinate synthetase deficiency, is a rare disease caused by a deficiency in argininosuccinate synthetase, an enzyme involved in excreting excess nitrogen from the body. There are mild and severe forms of the disease, which is one of the urea cycle disorders.

References

  1. 1 2 3 4 5 6 Donovan, Kathleen; Guzman, Nilmarie (August 8, 2022). "Ornithine Transcarbamylase Deficiency". StatPearls Publishing. PMID   30725942 . Retrieved October 22, 2023.
  2. ↑ Lichter-Konecki, Uta; Caldovic, Ljubica; Morizono, Hiroki; Simpson, Kara; Mew, Nicholas Ah; MacLeod, Erin (May 26, 2022). "Ornithine Transcarbamylase Deficiency". University of Washington, Seattle. PMID   24006547 . Retrieved October 22, 2023.
  3. ↑ "Ornithine transcarbamylase deficiency: MedlinePlus Genetics". MedlinePlus. October 1, 2017. Retrieved October 22, 2023.
  4. 1 2 3 4 5 Wraith, J. E. (2001). "Ornithine carbamoyltransferase deficiency". Archives of Disease in Childhood. 84 (1): 84–88. doi:10.1136/adc.84.1.84. PMC   1718609 . PMID   11124797.
  5. 1 2 3 4 5 Walker, V. (2009). "Ammonia toxicity and its prevention in inherited defects of the urea cycle". Diabetes, Obesity and Metabolism. 11 (9): 823–835. doi:10.1111/j.1463-1326.2009.01054.x. PMID   19531057. S2CID   25998574.
  6. 1 2 3 4 5 6 7 8 Lichter-Konecki, U.; Caldovic, L.; Morizono, H.; Simpson, K.; Pagon, R. A.; Adam, M. P.; Bird, T. D.; Dolan, C. R.; Fong, C. T.; Stephens, K. (1993). "Ornithine Transcarbamylase Deficiency". PMID   24006547.{{cite journal}}: Cite journal requires |journal= (help)
  7. 1 2 3 4 5 6 7 "#311250 - Ornithine Transcarbamylase Deficiency, Hyperammonemia Due To". Johns Hopkins University . Retrieved 2014-01-01.
  8. ↑ "Human ornithine transcarbamylase (OTC) mRNA, complete coding sequence". US National Library of Medicine.{{cite web}}: Missing or empty |url= (help)
  9. ↑ Deakin, C. T.; Alexander, I. E.; Kerridge, I. (2009). "Accepting Risk in Clinical Research: Is the Gene Therapy Field Becoming Too Risk-averse?". Molecular Therapy. 17 (11): 1842–1848. doi:10.1038/mt.2009.223. PMC   2835028 . PMID   19773741.
  10. 1 2 Morioka, D.; Kasahara, M.; Takada, Y.; Shirouzu, Y.; Taira, K.; Sakamoto, S.; Uryuhara, K.; Egawa, H.; Shimada, H.; Tanaka, K. (2005). "Current role of liver transplantation for the treatment of urea cycle disorders: A review of the worldwide English literature and 13 cases at Kyoto University". Liver Transplantation. 11 (11): 1332–1342. doi:10.1002/lt.20587. PMID   16237708. S2CID   25787334.
  11. ↑ Maestri, N. E.; Clissold, D.; Brusilow, S. W. (1999-03-01). "Neonatal onset ornithine transcarbamylase deficiency: A retrospective analysis". The Journal of Pediatrics. 134 (3): 268–272. doi: 10.1016/s0022-3476(99)70448-8 . ISSN   0022-3476. PMID   10064660.
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